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PubMedDate not supplied

Novel therapies targeting vascular endothelium.

Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature may improve the long-term outcome in healthy individuals, high-risk subjects, or patients with advanced atherosclerosis. Several therapeutic strategies are now available, targeting both the synthesis and oxidative inactivation of nitric oxide (NO) in human vasculature. Statins seem to be currently the most powerful category of these agents, improving endothelial function and decreasing cardiovascular risk after long-term administration. Other cardiovascular agents improving endothelial function in humans are angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, which increase NO bioavailability by modifying the rennin-angiotensin-aldosterone system. Newer therapeutic approaches targeting endothelial dysfunction in specific disease states include insulin sensitizers, L-arginine (the substrate for endothelial NO synthase [eNOS]) as well as substances that target eNOS "coupling," such as folates or tetrahydrobiopterin. Although there are a variety of strategies to improve NO bioavailability in human endothelium, it is still unclear whether they have any direct benefit at a clinical level.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Targeted therapy of respiratory syncytial virus by 2-5A antisense.

Respiratory syncytial virus is a leading cause of respiratory disease in infants, young children, immunocompromized patients, and the elderly. Previous work has shown that RNase L, an antiviral enzyme of the interferon system, can be recruited to cleave RSVgenomic RNA by attaching tetrameric 2' 5'-linked oligoadenylates (2 5A) to an antisense oligonucleotide complementary to repetitive intergenic sequences within the RSV genome (2 5A antisense). RBI034, a 2'-O-methyl RNA-modified analogue of the 2 5A anti-RSV compound, was found to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L- and sequence-specific manner. RBI034s efficacy in suppressing RSV replication in cell culture is 50 to 100 times better than ribavirin, the only approved drug for RSV infection. Here we show that the activity of 2 SA antisense compound can be further enhanced by a combination treatment with interferon or ribavirin. The anti-RSV activity resulting from combination treatment is more potent than either treatment alone. We also demonstrate that RBI034 is effective against RSV in three different species: mice, cotton rats, and African green monkeys.

Animals↗
PubMed2001

Cleavable linkers to enhance selectivity of antibody-targeted therapy of cancer.

Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to radionuclides to deliver radiation selectively to tumors. However, radiolabeled proteins deposit radioactivity in normal organs that metabolize or conserve proteins and peptides, primarily liver and kidneys. To accelerate the clearance of radioactivity from normal tissues, linkers between the antibody or antibody fragment and the radioactive moiety have been designed for cleavage in the liver and kidneys, to liberate low molecular weight radioactive species for rapid excretion. Modest success in improving the tumor-to-liver and tumor-to-kidney radiation dose ratios have been achieved in preclinical studies. Such changes when taken to clinical studies have suggested useful impact on therapeutic work. Recent advances in the development of cleavable linkers are described.

Animals↗
PubMed2004

Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma.

OBJECTIVES: The aim of this study was to evaluate the response- and treatment-related toxicity for patients with unresectable hepatocellular carcinoma (HCC) treated with 131I-Hepama-1 mAb (DGDK-1). MATERIALS AND METHODS: Seeking approval for the use of 131I-hepama-1 mAb, 32 patients with unresectable HCC were divided into 5 groups to take part in the Phase I clinical trial study. Systemic reactions and acute toxicity were evaluated weekly for at least 45 days following treatment with an intravenous injection of 10 mg of antibody radiolabeled with 740-3700 MBq (20-100 mCi), divided into 5 groups. RESULTS: No patients demonstrated any evidence of fever, severe side effects, or impairments of important organs, such as the lung, liver, and heart. During, and for 45 days after, the treatment, most of their routine examinations of blood, functions of liver and kidneys, and the thyroid hormone were all normal. Hypothyroidism was not observed during the course of monitoring. None of the 32 patients developed human antimurine antibodies (HAMA) within 15 days of therapy; however, 82% of patients were HAMA-positive by 45 days of therapy. According to the pilot study of prognosis, survival from the start of radioimmunotherapy (RIT) was a median of 4 months, and the 1-year survival rate was 31%. The median survival time of 15 patients without metastases was 10 months, and the 1-year survival rate was 60%. Of alpha-fetoprotein (AFP)-positive patients, 75% of AFP levels decreased by at least 50% or became normal. Of all patients, 84% showed an improved Eastern Cooperative Oncology Group (ECOG) performance status. CONCLUSION: This phase I clinical trial demonstrated that it was safe to use 131I-hepama- 1 mAb by peripheral intravenous administration. The recommended dose of DGDK-1 for clinical use is 1480-2960 MBq/10 mg.

Adult↗
PubMed2005

The potential use of 99mTc-MDP bone scans to plan high-activity 186Re-HEDP targeted therapy of bony metastases from prostate cancer.

Patients with skeletal metastases from hormone-refractory prostate cancer have shown variable responses to high-activity therapy with (186)Re-HEDP and peripheral stem cell support. In this paper, we report on the use of a novel technique to compare sequential planar images acquired post-(186)Re-HEDP therapy administration with pretherapy diagnostic (99m)Tc-MDP scans, to evaluate the turnover of the radiopharmaceutical in normal and abnormal bone. It was found that the activity in normal (i.e., disease-free) segments of the spine demonstrates a faster effective decay than that of the metastases, with the latter showing only physical decay. This study showed, for the first time, a detailed correlation in the behavior of the (99m)Tc-MDP and (186)Re-HEDP images, encouraging the possibility of using the pretherapy 99mTc-MDP scan for estimations of absorbed doses to be delivered by prescribed activities of (186)Re-HEDP.

Bone Neoplasms↗
PubMed2005

Evaluation of the therapeutic response to In-111-DTPA octreotide-based targeted therapy in liver metastatic neuroendocrine tumors according to CT/MRI/US findings.

Thirteen (13) patients with liver neuroendocrine carcinomas metastases, positive for somatostatin receptors, confirmed by scintigraphy were infused with 4070-7030 MBq per session of In-111-octreotide after selective hepatic catheterization, exploiting the catastrophic activity of Indium Auger and Internal Conversion electron emission on cell DNA. Evaluation of the treatment was assessed by ultrasonography (US) as well as by computed tomography and/or magnetic resonance imaging scans. US appears to be the imaging procedure of choice because the examination is sensitive for evaluating lesions' edema and cystic components, provides precise measurement of tumor size, and is inexpensive. Degeneration US signs were classified in stage I (an echolucent rim in the periphery of the lesion), stage IIa (lesion with large cystic spaces), stage IIb (tiny cystic spaces) and stage III (absorption of the cystic component or stable cystic remnants).

Adult↗
PubMed2003

Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer.

BACKGROUND: Standard anti-proliferative chemotherapy is relatively ineffective against slowly proliferating androgen-independent prostate cancer cells within metastatic sites. In contrast, the lipophilic cytotoxin thapsigargin, which causes apoptosis by disrupting intracellular free Ca2+ levels, is effective against both proliferative and quiescent (i.e., G0-arrested) cells. However, thapsigargin's mechanism of action indicates that it is unlikely to be selective for cancer cells or prostate cells. METHODS: We coupled a chemically modified form of thapsigargin, L12ADT, to a peptide carrier that is a substrate for the prostate-specific antigen (PSA) protease to produce a soluble, cell-impermeant latent prodrug that is specifically activated extracellularly within metastatic prostate cancer sites by PSA. We analyzed the kinetics of PSA hydrolysis of the prodrug, the in vitro cytotoxicity of the prodrug against PSA-producing LNCaP human prostate cancer and PSA non-producing HCT-116 human colon cancer cells, and the in vivo pharmacokinetics of the prodrug in mice. We also analyzed antitumor efficacy of the prodrug in nude mice xenograft models of prostate cancer (using LNCaP cells) and renal carcinoma (using human SN12C cells). RESULTS: The L12ADT peptide prodrug was hydrolyzed efficiently by PSA, was selectively toxic to PSA-producing prostate cancer cells in vitro, and was stable in human plasma. A single dose of 7 mg/kg resulted in a peak serum prodrug concentration of 15.4 +/- 1.1 microM and a half-life of approximately 2.8 hours. Over 24 hours, less than 0.5% of free L12ADT was observed in plasma. Levels of prodrug and liberated L12ADT in prostate cancer xenograft tumors were approximately eightfold and sixfold, respectively, higher than the in vitro LD50s. Prostate cancer xenograft tumors in mice treated with prodrug by intravenous administration were growth-inhibited without substantial host toxicity. Continuous subcutaneous prodrug administration in mice produced complete growth inhibition of established PSA-producing prostate cancer xenograft tumors but had no effect on PSA non-producing renal carcinoma xenograft tumors. CONCLUSION: Further development of PSA-activated thapsigargin prodrugs as therapy for metastatic prostate cancer is warranted.

Animals↗
PubMed1991

Psychology in primary health care: effects of brief targeted therapy on children's medical care utilization.

Evaluated the impact of psychological treatment for 93 children (ages 1-15) with common behavior, toilet, school, and psychosomatic problems. Children and parents, who were members of a health maintenance organization, had 1-6 visits to a primary care-based psychological consultation service. Individualized treatment was guided by problem-specific behavioral protocols. Parent outcome and behavior checklist ratings indicated improvement or resolution for 74% of children and high satisfaction with the psychological service. Children's use of medical services, especially acute primary care visits, was reduced during the year after treatment; a matched comparison group's use was unchanged. Addressing children's unmet mental health needs reduces medical care utilization. A primary health care model of psychological services provides an integrated system for serving the health and mental health needs of children.

Adolescent↗